Alterations in the gut microbiome and metabolism profiles reveal the possible molecular mechanism of renal injury induced by hyperuricemia in a mouse model of renal insufficiency

<b>Objectives:</b> To investigate the role of the intestinal flora and metabolites in the development of hyperuricemic renal injury in chronic kidney disease (CKD).<b>Methods:</b> Unilaterally nephrectomized mice were fed with adenine and potassium oxonate for 9 weeks. HE staining combined with plasma biochemical indicators was used to evaluate renal pathological and functional changes. We conducted 16S rRNA sequencing and untargeted metabolomics on feces and plasma samples to reveale changes in intestinal microbiota and metabolites.<b>Result:</b> Our analysis revealed significant differences in 15 bacterial genera, with 7 being upregulated and 8 being downregulated. Furthermore, metabolomic analysis revealed changes in the distribution of amino acid and biotin metabolites in basic metabolic pathways in both feces and serum. Specifically, differentially abundant metabolites in feces were associated primarily with histidine metabolism; the biosynthesis of phenylalanine, tyrosine, and tryptophan; and tyrosine metabolism. In plasma, the differentially abundant metabolites were involved in multiple metabolic pathways, including aminoacyl-tRNA biosynthesis; glycine, serine, and threonine amino acid metabolism; valine, leucine, and isoleucine biosynthesis; tyrosine biosynthesis and metabolism; biotin metabolism; and taurine and hypotaurine metabolism. Furthermore, correlation analysis revealed that <i>Akkermansia, UCG-005, Lachnospiraceae_NK4A136_group, Lactococcus, and Butymonas</i> were associated with various differentially abundant metabolites as well as renal function, oxidative stress, and mitophagy. The changes in the intestinal flora observed in hyperuricemia may lead to imbalances in amino acid and biotin metabolism in both the intestine and host, ultimately affecting oxidative stress and mitophagy in mice and accelerating the progression of CKD.<b>Conclusion: </b>Our findings provide insights into a potential pathogenic mechanism by which hyperuricemia exacerbates renal injury in mice with renal insufficiency. Understanding these pathways may offer new therapeutic strategies for managing hyperuricemic renal injury in CKD patients.

**研究目标**：旨在探讨肠道菌群及其代谢产物在慢性肾脏病（chronic kidney disease, CKD）合并高尿酸血症性肾损伤发生发展中的作用。
**研究方法**：将单侧肾切除小鼠予以腺嘌呤与氧嗪酸钾喂养9周。采用苏木精-伊红染色（HE staining）结合血浆生化指标，评估肾脏病理与功能变化。我们对粪便及血浆样本开展16S rRNA测序与非靶向代谢组学分析，以揭示肠道菌群与代谢产物的改变情况。
**研究结果**：本分析显示，共有15个细菌属存在显著差异，其中7个属表达上调，8个属表达下调。进一步代谢组学分析发现，粪便与血清中基础代谢通路的氨基酸及生物素代谢产物分布发生改变。具体而言，粪便中的差异富集代谢产物主要与组氨酸代谢、苯丙氨酸、酪氨酸及色氨酸生物合成，以及酪氨酸代谢相关。在血浆中，差异富集代谢产物涉及多条代谢通路，包括氨酰-tRNA生物合成、甘氨酸、丝氨酸与苏氨酸代谢、缬氨酸、亮氨酸与异亮氨酸生物合成、酪氨酸生物合成与代谢、生物素代谢，以及牛磺酸与次牛磺酸代谢。此外，相关性分析显示，阿克曼菌属（Akkermansia）、UCG-005、毛螺菌科_NK4A136_group（Lachnospiraceae_NK4A136_group）、乳球菌属（Lactococcus）及布特曼菌属（Butymonas）与多种差异富集代谢产物及肾功能、氧化应激、线粒体自噬均存在关联。高尿酸血症小鼠的肠道菌群改变可能导致肠道与宿主的氨基酸及生物素代谢失衡，最终影响小鼠体内氧化应激与线粒体自噬过程，加速CKD进展。
**研究结论**：本研究结果为高尿酸血症加重肾功能不全小鼠肾损伤的潜在致病机制提供了新的见解。阐明上述通路可为慢性肾脏病合并高尿酸血症性肾损伤患者的临床管理提供全新治疗策略。